The Ras-related Rho family of small GTPases is involved in a wide variety of cellular processes, including the regulation of the actin cytoskeletal organization, cell-to-cell or cell-to-extracellular matrix adhesion, intracellular membrane trafficking, gene transcription, apoptosis and cell cycle progression. Like the GTPase, Ras, the Rho family of GTPases exist in an inactive, GDP-bound and an active, GTP-bound conformation. Rho GTPases are activated by a class of positive regulators, the Dbl family guanine nucleotide exchange factors (GEFs1) that catalyze the release of bound GDP and facilitate the binding of GTP, whereas deactivation of Rho proteins is achieved through their intrinsic GTP-hydrolytic activities that are further stimulated by a class of negative regulators, the GTPase-activating proteins (GAPs). A third class of regulators of Rho GTPases, the Rho GDP-dissociation inhibitors, can negatively impact Rho protein activities by sequestering them in the GDP-bound state and preventing effective cycling between the two conformational states. Upon binding to GTP, Rho GTPases may further interact with an array of potential effector molecules to elicit cellular responses.
It has become increasingly clear that Rho proteins play important roles in many aspects of cancer development and each member of the Rho family may be involved to a different extent at different tumor progression stages. For example, it was shown that constitutively active RhoA has oncogenic potential and RhoA acts as a signaling component in Ras-induced transformation. Furthermore, RhoA promotes the invasiveness of rat hepatoma cells and induces metastasis of NIH 3T3 fibroblasts, while RhoC was revealed as a key regulator of migration and metastasis in a human melanoma cell line. Upon introduction into normal mammalian epithelial cells, RhoC readily caused transformation and invasion, leading to an inflammatory breast cancer cell phenotype. On the other hand, RhoB is required for the apoptotic responses induced by farnesyltransferase inhibitors or DNA damaging agents and may have a suppressor or negative modifier function in cancer progression. Unlike Ras, there are no reports of mutation-caused constitutive activation of Rho proteins in tumors. Recent studies of primary human tumors revealed that many Rho GTPases, including RhoA and RhoC, are highly expressed in a variety of cancer types such as colon, lung, testicular germ cell, head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, and inflammatory breast, and in some cases, the Rho protein upregulation and/or overexpression correlates with poor prognosis. These observations help put Rho proteins in a lineup of potential molecular targets for anti-cancer therapy.